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P R O T O C O L

(Full-Scale Clinical Trial Phase III)

for the

Diabetes Control and Complications Trial

Prepared by

Diabetes Control and Complications Trial Research Group

June 1987

Revised June, 1988

Approved by DCCT Steering Committee February 1986

Reviewed and approved by DSQ April 1986

Forwarded to NIDDK July 1986

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TABLE OF CONTENTS

ABBREVIATIONS USED ........................ .......................... ........................... ........................... .................ISUMMARY..............................................................................................................................................II1. INTRODUCTION ........................ .......................... ........................... ........................... .........................1

1.1 SCOPE AND IMPACT OF DIABETES.................................................................................................11.2 RATIONALE FOR THE DCCT STUDY QUESTION ..............................................................................21.3 BACKGROUND ............................................................................................................................3

1.4 FUTURE DIRECTIONS ..................................................................................................................52. OBJECTIVES AND DESIGN........................ .......................... ........................... ........................... .......7

2.1 OBJECTIVES...............................................................................................................................72.2 DESIGN .....................................................................................................................................8

3. SAMPLE SIZE...................................................................................................................................113.1 INTRODUCTION .........................................................................................................................113.2 NATURAL HISTORY OF RETINOPATHY ..........................................................................................113.3 STUDY DURATION AND SAMPLE SIZE ..........................................................................................123.4 POWER....................................................................................................................................133.5 INTERIM ASSESSMENTS .............................................................................................................153.6 SUMMARY ................................................................................................................................15

4. SUBJECT SELECTION AND RECRUITMENT....................... ........................... ........................... .....194.1 INTRODUCTION .........................................................................................................................19

4.2 ELIGIBILITY CRITERIA ................................................................................................................194.2.1Eligibility Criteria Applicable to All Subjects ....................................................................194.2.2For Subjects Without Retinopathy ..................................................................................194.2.3For Subjects With Minimal Background Retinopathy ...................................................... 20

4.3 EXCLUSION CRITERIA ................................................................................................................204.3.1Exclusion Criteria Applicable to All Subjects...................................................................204.3.2Exclusion Criteria for Subjects Without Retinopathy .......................................................234.3.3Additional Exclusion Criteria for Subjects With Minimal Background Retinopathy ...........24

4.4 RECRUITMENT ..........................................................................................................................245. INFORMED CONSENT ........................... ........................... ........................... ........................... .........25

5.1 GENERAL PRINCIPLES ...............................................................................................................255.2 SEQUENCE OF PROCEDURES .....................................................................................................26

6. PRE-RANDOMIZATION EVALUATION.............................................................................................276.1 GENERAL PRINCIPLES ...............................................................................................................276.2 LABORATORY ...........................................................................................................................276.3 OPHTHALMOLOGIC....................................................................................................................276.4 RENAL .....................................................................................................................................276.5 NEUROLOGIC ...........................................................................................................................286.6 CARDIOVASCULAR ....................................................................................................................286.7 PSYCHOLOGICAL ......................................................................................................................296.8 COMPLIANCE/ADHERENCE.........................................................................................................296.9 DIETARY ..................................................................................................................................306.10 EXAMINATION RESULTS .............................................................................................................30

7. RANDOMIZATION ......................... ........................... ........................... ........................... ..................327.1 PHASE II RANDOMIZATION .........................................................................................................327.2 PHASE III RANDOMIZATION ........................................................................................................32

7.2.1Stratification...................................................................................................................32

7.2.2Randomization Sequences ............................................................................................327.2.3Pace of Randomization..................................................................................................33

7.3 MECHANICS OF RANDOMIZATION ................................................................................................337.4 INELIGIBLE SUBJECTS WHO ARE RANDOMIZED ............................................................................33

8. METABOLIC CONTROL......................... ........................... ........................... ........................... .........348.1 INTERVENTION STRATEGY IN THE STANDARD GROUP....................................................................34

8.1.1Intervention Strategy......................................................................................................348.1.2Insulin............................................................................................................................358.1.3Diet................................................................................................................................358.1.4Exercise ........................................................................................................................358.1.5Self Monitoring/Glucose.................................................................................................35

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8.1.6Self Monitoring/Ketone...................................................................................................368.1.7Clinic Visits ....................................................................................................................368.1.8Educational Program ..................................................................................................... 368.1.9Protection of Subjects .................................................................................................... 36

8.2 INTERVENTION STRATEGY IN THE EXPERIMENTAL GROUP .............................................................368.2.1General Guidelines ........................................................................................................ 378.2.2Insulin............................................................................................................................378.2.3Diet................................................................................................................................38

8.2.4Exercise ........................................................................................................................388.2.5Monitoring/Ketones........................................................................................................388.2.6Blood Glucose Monitoring..............................................................................................388.2.7Clinic Contacts...............................................................................................................388.2.8Protection of Subjects .................................................................................................... 39

8.3 GENERAL PROCEDURES TO MAXIMIZE ADHERENCE TO PROTOCOL ................................................399. PROCEDURES FOR FOLLOW-UP VISITS........................ ........................... ........................... .........40

9.1 GENERAL PRINCIPLES ...............................................................................................................409.2 BLOOD GLUCOSE CONTROL.......................................................................................................409.3 OPHTHALMOLOGIC....................................................................................................................409.4 RENAL .....................................................................................................................................419.5 NEUROLOGIC ...........................................................................................................................419.6 CARDIOVASCULAR ....................................................................................................................41

9.7 PSYCHOLOGICAL ......................................................................................................................429.8 COMPLIANCE/ADHERENCE.........................................................................................................429.9 DIETARY ..................................................................................................................................429.10 EXAMINATION RESULTS .............................................................................................................429.11 MISSED VISITS .........................................................................................................................429.12 TRANSFER ...............................................................................................................................43

10. INTERNAL MONITORING...............................................................................................................4410.1 GENERAL PRINCIPLES ...............................................................................................................4410.2 RESPONSIBILITY FOR MONITORING .............................................................................................4410.3 PERFORMANCE MONITORING .....................................................................................................45

10.3.1Clinical Centers............................................................................................................4510.3.2Central Units................................................................................................................4510.3.3Coordinating Center.....................................................................................................46

10.4 CORRECTION OF DEFICIENCIES ..................................................................................................4611. INTERCURRENT EVENTS..............................................................................................................47

11.1 DEFINITION OF INTERCURRENT EVENTS ......................................................................................4711.2 GENERAL PRINCIPLES ...............................................................................................................4711.3 GUIDELINES FOR THE MANAGEMENT OF INTERCURRENT EVENTS ...................................................47

12. CHANGES IN TREATMENT............................................................................................................4812.1 INTRODUCTION .........................................................................................................................4812.2 MODIFICATION OF THE EXPERIMENTAL TREATMENT PROTOCOL .....................................................4812.3 MODIFICATION OF THE STANDARD TREATMENT PROTOCOL ...........................................................4812.4 REVIEW OF MODIFICATIONS .......................................................................................................4912.5 DEVIATION FROM TREATMENT PROTOCOLS .................................................................................4912.6 REVIEW OF DEVIATIONS ............................................................................................................4912.7 TRANSFER TO INACTIVE STATUS.................................................................................................4912.8 REVIEW OF TRANSFER TO INACTIVE STATUS................................................................................49

13. RESULTS AND STATISTICAL ANALYSES....................................................................................5013.1 GENERAL PRINCIPLES ...............................................................................................................5013.2 BASELINE RESULTS AND ANALYSES ............................................................................................5013.3 OUTCOME VARIABLES ...............................................................................................................5013.4 ANALYSIS PLAN ........................................................................................................................5313.5 INTERIM ANALYSES ...................................................................................................................53

14. PUBLICATIONS AND PRESENTATIONS.......................................................................................5514.1 INTRODUCTION .........................................................................................................................5514.2 DUTIES OF THE PUBLICATIONS AND PRESENTATIONS COMMITTEE ..................................................5514.3 IMPLEMENTATION......................................................................................................................56

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15. ANCILLARY STUDIES....................................................................................................................5715.1 INTRODUCTION .........................................................................................................................5715.2 DEFINITION OF AN ANCILLARY STUDY..........................................................................................57

15.2.1Reason for Requirement of Approval ........................................................................... 5715.3 LEVELS OF APPROVAL REQUIRED FOR ANCILLARY STUDIES ..........................................................5715.4 FUNDING OF ANCILLARY STUDIES ...............................................................................................5815.5 PUBLICATION OF ANCILLARY STUDY RESULTS..............................................................................5815.6 IMPLEMENTATION......................................................................................................................58

16. PROTOCOL CHANGES..................................................................................................................5916.1 INTRODUCTION .........................................................................................................................5916.2 STEERING COMMITTEE POLICY...................................................................................................5916.3 PROCEDURES...........................................................................................................................59

17. ORGANIZATION.......................... ........................... ........................... ........................... ..................6017.1 INTRODUCTION .........................................................................................................................6017.2 STRUCTURE.............................................................................................................................6017.3 MORBIDITY/MORTALITY CLASSIFICATION COMMITTEE ...................................................................64

18. DISPOSITION OF DOCUMENTS, DATA, AND MATERIALS .......................... ........................... .....6618.1 DOCUMENTS ............................................................................................................................6618.2 DATA FORMS ...........................................................................................................................6618.3 TAPES OF DATA AND ANALYSIS FILES .........................................................................................6618.4 LABORATORY SPECIMENS..........................................................................................................66

18.5 PHOTOGRAPHS AND OTHER MATERIALS......................................................................................6618.6 POLICY OF EXTERNAL DISTRIBUTION OF DOCUMENTS DURING THE CONDUCT OF THE STUDY ...........67APPENDIX A.........................................................................................................................................68APPENDIX B.........................................................................................................................................74

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ABBREVIATIONS USED

CBL............... Central Biochemistry Laboratory

CHL............... Central Hemoglobin A1c Laboratory

CMG.............. Clinic Monitoring Group

CORU ........... Central Ophthalmic Reading Unit

CSII............... Continuous subcutaneous insulin infusion

DCCT............ Diabetes Control and Complications Trial

DRS .............. Diabetic Retinopathy Study

DSQ.............. Data. Safety, and Quality Review Group

ETDRS.......... Early Treatment Diabetic Retinopathy Study

HbA1c........... Hemoglobin A1c

IDDM............. Insulin dependent diabetes mellitus

Ma................. Microaneurysm

MDI ............... Multiple Daily Injection

NHLBI ........... National Heart, Lung and Blood Institute

NIAMDD........ National Institute of Arthritis, Metabolism and Digestive Diseases

NIDDK........... National Institute of Diabetes and Digestive and Kidney Diseases

NIH................ National Institutes of Health

UA................. Urinalysis

UC................. Urine culture

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SUMMARY

The purpose of the study entitled the Diabetes Control and Complications Trial (DCCT)is to compare the effects of two treatment regimens designed to produce different levels of

metabolic control on the clinical course of early vascular complications in persons with insulin-dependent diabetes mellitus (IDDM). The treatment regimens are called experimental andstandard. These terms are used to denote an intensive insulin regimen and a conventionalinsulin regimen respectively (Section 8). Blood glucose and hemoglobin A1c will be used asprimary indicators of metabolic control. Diabetic retinopathy will be the principal outcomeassessed because it can be reliably quantitated and its rate of progression determined in areasonable number of years. Other outcomes will include diabetic nephropathy, diabeticneuropathy and cardiovascular events or their known or putative risk factors/

The Protocol describes a randomized, controlled, clinical trial to determine:

whether a clinically and statistically significant difference in the level of blood

glucose control between standard and experimental therapy groups as assessed by hemoglobinA1c and blood glucose measurements will result in a clinically and statistically significantdifference in the rate of appearance and progression of the early vascular complications ofinsulin-dependent diabetes mellitus; and

whether there is a difference in the utility, subject acceptability and safety ofexperimental therapy compared to standard therapy in the management of persons with IDDM>

The DCCT will focus concurrently on two categories of IDDM subjects: those who haveno evidence of background retinopathy and those who have minimal background retinopathy.

At time of entry into the study, subjects with documented IDDM of 1-15 years durationwill be 13-39 years of age; have hemoglobin A1c greater than three standard deviations abovethe mean sample of the nondiabetic population have either no evidence, or a minimal degree ofbackground retinopathy; and have no serious co-existing disease (Section 4). Subjects withoutretinopathy must have a duration of IDDM of at least one year but no more than five years andno microalbuminuria. Subjects with minimal retinopathy must have a duration of IDDM of atleast one year but no more than 15 years and less than 200 mg/day of microalbuminuria.

Investigators at each clinical center will determine, through a standardized history andphysical examination and a series of biochemical and psychological/behavioral determinations,whether a potential study subject is eligible for inclusion in the DCCT (Section 6). Specificcriteria of eligibility for, and exclusion from, entrance into the study have been developed.Subjects who are found to be eligible for the study will undergo additional baseline assessmentsbefore randomization into a treatment group. The eligibility and baseline assessments willinclude hemoglobin A1c determination, blood glucose profile, a standardized ophthalmologicexamination including stereo fundus photography and fluorescein angiography, andstandardized renal, neurologic, cardiovascular, psychological and compliance/adherenceassessments. Fully informed written consent will be obtained from each participant prior toeligibility screening and again prior to randomization (Section 5).

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hemoglobin A1c and blood glucose profiles will be made quarterly. Stereo fundus photographywill be performed at baseline and semiannually thereafter; a standardized ophthalmologicexamination including visual acuity tests will be conducted yearly. Standardized psychological,neurobehavioral and compliance/adherence assessments will be made periodically (seeSections 9.6 and 9.7. Additional visits will be scheduled as needed for clinical care of thesubject.

General principles are specified for the management of diabetic ketoacidosois,hypoglycemia, pregnancy and other intercurrent events (Section 11). The Protocol alsodescribes procedures for changes in treatment (Section 12) and for protocol changes (Section16). Policies to be employed in the statistical analysis of the data are presented in Section 13.

Mechanisms for assuring quality control and for monitoring the performance of all DCCTcomponents on a regular basis have been established within the DCCT structure includingprograms for central laboratory quality control and surveillance of the clinical centers and theCoordinating Center. Two groups are specified which are advisory to the NIDDK and areotherwise external to, and independent of, the DCCT: the Policy Advisory Group (PAG) and theData, Safety, and Quality Review Group (DSQ) (Section 17).

This Protocol is a statement of the goals and policies for Phase III of the DCCT. Thedetails of the implementation of the Phase III study are given in the DCCT Manual ofOperations.

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1. INTRODUCTION

1.1 Scope and Impact of Diabetes

Diabetes is a major public health

problem.1

Approximately 5.8 million persons, about 2.6%of the United States population, have been diagnosed by a physician as diabetic. The insulin-dependent form of diabetes mellitus (IDDM) is estimated to be approximately 10% of all knowncases, but virtually all diabetes diagnosed before age 20 is of this type.

Diabetes is not a benign disease. The complications of diabetes may involve every tissueof the body, but the blood vessels, nerves, kidneys, and eyes are particularly susceptible.Diabetes causes:

12% of all new cases of blindness;

25% of all kidney failure;

40% of all non-traumatic amputations of the foot and leg among adults.

Additionally, diabetes is one of the four major risk factors for cardiovascular disease. Heartdisease, hypertension, and stroke are two to six times more likely to occur in persons withdiabetes.

While complications occur in all types of diabetes, persons with IDDM may account for adisproportionate share of blindness, kidney failure, problems associated with child bearing, andpremature deaths. In those with IDDM:

3% are legally blind after 15 years of diabetes;

12% are blind after 30 or more years of diabetes;

30% have diabetic nephropathy after 15 years of diabetes;

2 to 7 times more prenatal and perinatal complications and 2 to 3 times morecongenital malformations occur in infants of diabetic mothers; and

12% are dead within 20 years after diagnosis of diabetes.

The United States ranks among the five nations in the world with the greatest mortality dueto diabetes. It is the seventh leading cause of death in the United States and accounts for 150,000

deaths annually. In persons with IDDM, the majority of early deaths are due to kidney andcardiovascular diseases. Above age 20, over half of the deaths occurring in people with IDDM aredue to kidney disease; this is about 500 times more frequent than in similarly aged nondiabeticpersons. Deaths attributable to cardiovascular disease are about 13 times higher in persons withIDDM than in nondiabetics of similar ages. The overall mortality rate for persons with IDDM is five

1

Extracted from statistics provided in "Diabetes in America, Diabetes Data Compiled 1984" by the NationalDiabetes Data Group, NIADDK, NIH.

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to 11 times greater than the rates for nondiabetics of the same age; however, the risk of deathmarkedly accelerates after age 25 to approximately 20 times that of nondiabetic persons.

Diabetes places a major drain on our health resources. Persons with diabetes have two tothree times as much disability as nondiabetics and spend over twice as many days in the hospitalas persons without this disease. Over 25% of all diabetics require hospitalization each year,

accounting for three million hospitalizations annually and about 30 million hospital days.Additionally, about 16 million visits to physicians are made each year by persons with diabetes. Itis the fourth leading cause of visits to general and family practice physicians.

Finally, the economic toll of diabetes has almost tripled in the ten years since the report ofthe National Commission on Diabetes. Excluding its complications, the cost in hours of work lostdue to disability and premature mortality and in medical and hospital costs is at least $14 billion.

While there is no known cure for diabetes, the future, nonetheless, looks promising forpeople with diabetes. Improved treatment approaches have been developed and others are underactive investigation. These new approaches may lead to even better methods of treatment thatwill reduce the occurrence of both the acute and long-term complications. Major research

advances in biomedical research have greatly expanded our understanding of the pathogenesis ofdiabetes and its complications. This enhanced knowledge may lead to the ability to preventdiabetes or its complications. Reducing the severity of diabetes will result in enormous savings inthe human toll exacted on persons with diabetes and their families as well as the costs to societydue to medical care, hospitalization, rehabilitation and economic losses due to shortened life-spans and lost days of work.

1.2 Rationale for the DCCT Study Question

One of the critical issues in diabetes mellitus has concerned the relationship betweenmetabolic control2 and the chronic complications of the disease. Controversy and debateregarding this relationship has been ongoing for 50 years.

Those who advocate the general use of rigid control (i.e., attempts to maintain bloodglucose as close to normal as possible) believe that there is sufficient evidence to support theclaim that such control lessens or delays the appearance of most chronic complications. Thosewho do not advocate the general use of rigid control contend that the evidence is inconclusive, thatrigid control increases the frequency and severity of potentially dangerous side effects (e.g.,hypoglycemia), and that there is some indication of potential harm (e.g., acute worsening of mildretinopathy).

Debate on the issue has centered largely on three questions:

whether, or to what extent, the chronic complications of diabetes are related to the

metabolic derangements which characterize insulin dependent diabetes mellitus;

2

As used in the Protocol, "metabolic control" should be understood to mean the entire spectrum ofmetabolic and hormonal derangements that comprise the syndrome known as insulin-dependent diabetesmellitus. Although blood glucose control is generally used as an indicator of overall metabolic control, thisis for simplicity and should not be interpreted as meaning that the DCCT investigators have equated thetwo.

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whether improvement of the abnormal metabolic state will lead to prevention oramelioration of the complications; and if so,

what level of metabolic control is necessary to prevent the development or amelioratethe progression of such complications.

Conduct of the controlled clinical trial needed to resolve this issue was impeded by lack ofa treatment which could achieve consistently lower blood glucose levels than those attainable withconventional therapy. In the late 1970's, technological advances in treatment approaches weremade which offered significant promise for enhanced metabolic control. Experience in theapplication of these technologies demonstrated that it was feasible to alter the level of controlachieved compared to more conventional treatment approaches. Given the capabilities availablein 1985, the DCCT will test whether therapies that enable alterations of metabolic control canchange the natural history of early vascular complications in persons with IDDM compared toconventional treatment approaches.

1.3 Background

In its report to the Congress in 1975, the National Commission on Diabetes recommendedthat the National Institute of Arthritis, Metabolism and Digestive Diseases(NIAMDD)3 and theNational Heart, Lung, and Blood Institute (NHLBI) initiate and support a five-year clinical study toassess the effect of treatment of IDDM on the development of microvascular complications.

In 1977, the NIDDK and NHLBI convened an ad hoc committee to consider whether, how,and when such a clinical trial should be initiated. In 1978, that committee issued its reportrecommending that such an undertaking was both ethical and feasible and that the Institutesshould proceed with a phased clinical trial to compare the effects of "strict" versus "conventional"treatment regimens. In attempting to effect this recommendation, it became clear that a conjointstudy of both macrovascular and microvascular complications would not be feasible due to majordifferences in the natural history of the two types of complications. Accordingly, it was agreed thatthe NIDDK would proceed alone with the study and that the study would focus on early vascularcomplications.

As the planning for the study proceeded, it became increasingly clear that significant andongoing progress in the development of new treatment approaches related to the metabolicaspects of diabetes had been made since the committee's report, notably the open loop devicesfor the delivery of insulin and methods for self monitoring of blood glucose concentration, and thatthese new technologies might offer considerable potential for achieving improved metabolicregulation. Furthermore, if they could be used in a controlled clinical trial, it might be possible tomake a more clear-cut distinction between treatment groups and, thus, provide a better basis forcomparison of the two treatment regimens. The NIDDK determined that initiation andimplementation of such a study should be delayed so that the trial could incorporate the most

current and effective methods of treatment.

In September 1980, the NIDDK convened a second group of advisors to reassess thetimeliness of initiating the study. This committee issued a report reaffirming the recommendationsof the first ad hoc advisory group to proceed with the study. It was further recommended thatdiabetic retinopathy be the principal outcome assessed in two separate groups of subjects: those3

In 1986, the name of the Institute was changed to National Institute of Diabetes and Digestive and KidneyDiseases (NIDDK).

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with no evidence of background retinopathy at entry (a primary prevention group) and those withevidence of minimal background retinopathy at entry (a secondary intervention group). Therationale for studying both groups concurrently was that the secondary intervention trial wouldhave the potential of showing a beneficial effect of one of the treatments sooner than a primaryprevention trial; however, a negative result from a secondary intervention trial would not addressthe question posed in a primary prevention trial. Accordingly, it was recommended that both trials

be undertaken simultaneously. The committee stipulated that the trial progress through sequentialphases which would include a feasibility study preliminary to a full-scale trial. It was directed thatthe feasibility study address the utility, subject acceptability, safety and efficacy of intensivetreatment regimens compared to conventional treatment regimens which might be suitable forapplication in a full-scale trial. The juncture between the feasibility study and the full-scale trialwas to serve as a major decision point at which time a detailed assessment of the results of thefeasibility study would be conducted by an independent group of expert advisors. The decisionregarding initiation of a full-scale, long-term clinical trial would be based on this advice. Thecommittee urged that the NIDDK proceed as quickly as possible to initiate the feasibility study.

Acting upon this recommendation, in 1981 the NIDDK issued a Request for ResearchCooperative Agreement Applications for clinical centers and a Request for Proposals for a Data

Coordinating Center willing to participate in a study consisting of the following four phases:

Phase I -- Planning (6-12 months)

Phase II -- Feasibility Study (2 years)

Phase III -- Full-Scale Clinical Trial (7-10 years)

Phase IV -- Data Analysis/Reporting (1 year)

Twenty-one clinical centers in the United States and Canada and a Data Coordinating Center weresubsequently selected to participate in the study on the basis of scientific peer review.

Phase I (Planning) was initiated in March 1982 for the purposes of designing the Phase IIProtocol (DCCT Research Group, 1986), assembling the Manual of Operations and establishingcertification requirements for the clinical centers, central laboratories and reading and coding unitspreparatory to recruitment of subjects. The nomenclature specified for the two treatment groups inthe DCCT was: experimental to denote the intensive treatment regimen and standard to denotethe conventional treatment regimen.

Phase II (Feasibility) commenced in August 1983 and was completed in March 1985. Thespecific objectives of Phase II were the following:

1. To determine whether a well-informed cohort of subjects, comprising both adolescents

and adults who fulfilled all the stringent eligibility criteria, could be recruited in areasonable period of time.

2. To determine whether both a clinically meaningful and statistically significant differencein the level of blood glucose control could be achieved between the randomly assignedstandard (conventional) and experimental (intensive) therapy groups, as assessed byhemoglobin A1c (HbA1c) and blood glucose measurements, while maintaining bothtreatment groups within acceptable ranges of glycemic control.

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3. To determine the safety of the two therapies with major emphasis on assessment of:symptoms attributable to hyperglycemia, episodes of ketoacidosis, and episodes ofhypoglycemia.

4. To determine whether the randomly assigned therapies would be equally acceptable tosubjects as assessed by measures of adherence to the randomly assigned therapies

over time and completeness of followup.

5. To determine whether biochemical and pathological characteristics of IDDM could bemeasured and documented with acceptable precision and accuracy.

Two hundred seventy-eight subjects were enrolled in the feasibility study. By March 1985,the data from 12 months of followup on all subjects had been collected (DCCT Research Group,1986). These data were independently reviewed by two separate expert advisory groups. Bothgroups found that by all essential criteria, the feasibility objectives had been met andrecommended that the NIDDK proceed with Phase III of the DCCT utilizing the protocol developedfor the feasibility study with appropriate modifications.

In October 1985, the NIDDK notified the DCCT Study Group that a decision had beenreached to proceed with Phase III, the full-scale clinical trial. In November 1985, a Request forResearch Cooperative Agreement Applications was issued for additional clinical centers toparticipate in Phase III. Six additional centers were selected on the basis of peer review bringingthe total number of participating clinical centers to 27 for Phase III of the DCCT.

1.4 Future Directions

The outcome of the DCCT will influence the course and direction of clinical management ofpersons with insulin-dependent diabetes. Recruitment of subjects will continue until the full cohortof 1400 is reached. It is planned that followup of all subjects will continue until the fifth anniversary

of the last subject randomized.

An independent external group of scientific peers will review all emerging study data atregular intervals for subject safety and data quality and report to a second body of independentscientific peers. The latter group is charged with recommending to the Director of NIDDK thecontinuation or termination of this study, a decision to be based on careful consideration of theinformation resulting from the emerging data.

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REFERENCES

1. The Diabetes Control and Complications Trial Research Group: The Diabetes Control andComplications Trial (DCCT). Design and Methodological Considerations for the FeasibilityPhase. Diabetes 35:530-545, May 1986.

2. The Diabetes Control and Complications Trial Research Group: The Diabetes Control andComplications Trial (DCCT). Results of the Feasibility Study (Phase II). Diabetes Care10:1-19, January-February 1987.

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2. OBJECTIVES AND DESIGN

2.1 Objectives

The major objective of the DCCT will be to compare the effect of an experimental and astandard approach to the control of blood glucose on early vascular complications in persons withIDDM.

Principal Objectives:

1. To compare the following separately for the

a) Primary Prevention Trial: Rate of onset and progression of diabetic retinopathy;and for the

b) Secondary Intervention Trial: Rate of progression of pre-existing mild non-

proliferative diabetic retinopathy.

2. To compare the rate of major adverse events associated with the treatment of diabetesor participation in the trial.

Other Objectives in Both Trials:

1. To compare the rate of onset and progression of nephropathy.

2. To compare the rate of onset and progression of neuropathy.

3. To compare the rate of onset and concomitant progression of retinopathy, neuropathy,

and nephropathy.

4. To compare the incidence of cardiovascular events and their known or putative riskfactors.

Operational Objectives in Both Trials:

1. To recruit and randomize the numbers of subjects required to provide adequatestatistical power for both trials.

2. To maintain both a clinically and statistically significant difference in the level of bloodglucose control between the randomly assigned standard and experimental therapy

groups as assessed by hemoglobin A1c (HbA1c) and blood glucose measurements.

3. In treatment of individual subjects in both groups to maintain clinical well-being, tomaintain glycemia below predefined limits, and to minimize the occurrence of severehypoglycemia.

4. To maintain acceptable levels of adherence to the randomly assigned standard andexperimental therapies as assessed by measures of adherence over time, includingcompleteness of followup.

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5. To monitor and maintain the precision and accuracy of theassessments of the biochemical and pathological characteristics of IDDM.

The variables to be employed to address all the above objectives will be defined more precisely inSection 13, Statistical Analyses.

Natural History Objectives:

To describe the natural history of IDDM among subjects who receive the experimentaltherapy and among subjects who receive the standard therapy. This includes the evaluation of theabove objectives within subgroups of subjects defined on the basis of age, gender, duration ofIDDM, entry C-peptide, level of blood glucose and HbA1c, blood pressure, renal status, serumlipids, and other factors suspected to be associated with the risks for the development ofcomplications of IDDM.

2.2 Design

In accordance with these objectives, the DCCT has the following design features:

1. All 278 subjects recruited for the feasibility study will continue to be followed untilcompletion of the study in either the primary or secondary trial as indicated by post-randomization stratification on the subjects baseline retinopathy status.

2. Additional subjects will be recruited over a period of three years and their eligibilitydetermined (see Section 4). Subjects without evidence of diabetic retinopathy suitablefor a primary prevention trial and subjects with evidence of minimal retinopathy (seesection 4) suitable for a secondary intervention trial will be recruited.

3. Eligible and consenting subjects in each of the clinical centers will be assigned

randomly to receive either standard or experimental therapy.

4. A total of 1400 subjects will be randomized within two retinopathy strata withapproximately equal numbers in each stratum.

5. This sample size provides power >0.91 to detect a 32.5 to 37.5% reduction in theannual hazard for the onset or progression of diabetic retinopathy allowing for 10% lossof followup and 20% nonadherence to assigned treatment.

6. For the primary prevention trial, the preferred outcome measure is a compellingclinically defined event such as proliferative diabetic retinopathy (PDR). However, theincidence of such an outcome in this population is low, even with the planned ten-year

followup. Therefore, the sample size required to achieve a statistically significant resultwould be excessive. Thus, a different outcome measure is needed. This measureneeds to accurately reflect the underlying physiological process of worsening ofretinopathy and have an event rate higher than that for PDR. Thus, the DCCT hasselected the appearance of any retinopathy, defined as the onset of persistentmicroaneurysms, as the outcome measure upon which the sample size is based.Therefore, the study has less power to detect treatment group differences at the moreclinically meaningful levels of retinopathy. Nevertheless, a treatment group difference

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with respect to the appearance of any retinopathy will be evaluated in consideration ofits consistency with a treatment effect at more clinically meaningful levels.

7. Standard therapy will consist of not more than two injections of insulin daily. The doseand insulin mixture will be determined on an individual basis by the physician. Clinicalwell-being is the first priority. Special efforts will be made to insure that the subjects

hemoglobin A1cdoes not exceed two standard deviations above the mean of asample of IDDM subjects (13.11%) and that all criteria for good clinical health are met.

8. Experimental therapy will permit the subject and his/her physician to choose eithermultiple daily injections of insulin (MDI) or a continuous subcutaneous infusion ofinsulin (CSII) or a combination. Both will employ frequent self blood glucose monitoringand will strive to maintain hemoglobin A1clevels within two standard deviations ofthe mean for a sample of persons without diabetes (6.05%, mean + 2 S.D.).

9, All subjects will be analyzed according to their original treatment assignment and allefforts will be made to treat subjects according to their assignment until the end of thestudy. Changes in treatment are discussed in Section 12.

10. .All subjects will be followed at least until the fifth year after enrollment in the study oruntil the study is terminated. Thus, some subjects will be followed for up to ten yearswhile others will be followed for less and varying lengths of time.

11. All study personnel are masked to study outcomes, therefore, two independentadvisory groups will review periodically the study results and are authorized torecommend to the NIDDK that the trial be terminated if the study objectives have beenmet. However, clinical thresholds for safety have been created and appropriatepersonnel will be alerted when a patient passes a threshold.

12. Clinical, physical, and biochemical evaluations will be conducted prior to randomization

and periodically during followup according to the schedule depicted in Table 2.1.

13. The two treatment regimens will, of necessity, be conducted in an unmasked manner.With the exception of HbA1c, all centrally determined outcome measurements willordinarily be masked from the investigator responsible for the treatment regimens andfrom the subjects. The results of these centrally determined outcome measurementsrelating to complications will be reported as "within acceptable limits" when notherapeutic intervention is indicated. In the event that an outcome measurement woulddictate a change in subject management, the results will be promptly communicated tothe responsible investigator who will inform the subject and institute appropriatetherapy.

Hemoglobin A1c values will be unmasked in the experimental group because thetreatment regimen is directed toward achieving specific values. Hemoglobin A1cvalues will ordinarily remain masked in the standard group because the treatmentregimen is not directed toward achieving specific values. However, in this group,subjects with HbA1c values that exceed the upper action limit of two standarddeviations above the mean of samples of IDDM subjects (13.11%) will be reportedmonthly to the investigator until the situation is corrected (see Section 8).

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Table 2.1 June 198

Diabetes Control and Complications TrialSchedule of Patient Evaluation for Endpoint Analyses

EXAMINATIONS BASELINE 1 YR 2 YR 3 YR 4 YR 5 YR 6 YR 7 YR 8 YR 9 YR orLAST

GENERALHistory and Physical Exam X X X X X X X X X X

BLOOD GLUCOSE CONTROLHome Blood Glucose Profile X X X X X X X X X X

(Baseline, quarterly, annually)HbA1c (Baseline, quarterly, annually) X X X X X X X X X X

OPHTHALMOLOGICVisual Acuity X X X X X X X X X XIntraocular Pressure X X X X X X X X X X

Slit Lamp X X X X X X X X X XOphthalmologic Exam X X X X X X X X X XStereo Fundus Photography (Baseline, semiannually, annually) X X X X X X X X X XStereo Fluorescein Angiography* X X X

RENALMicroalbuminuria X X X X X X X X X XCreatinine Clearance X X X X X X X X X XI-125 Iothalamate Clearance X X XSerum Creatinine, Albumin X X X X X X X X X XUrine Creatinine, Albumin X X X X X X X X X XSodium urea and nitrogen and urine creatinine 24-hour urine collection) X X X X

NEUROLOGICStandardized Symptom History & Physical Exam X X XAutonomic Nervous System Function Tests (RR-Variation on EKG) X X X X XNoninvasive Nerve Conduction X X X

CARDIOVASCULARHistory & Physical (Including Peripheral Vascular History & Physical Exam)

X X X X X X X X X XBlood Pressure, Pulse (Baseline, quarterly, annually) X X X X X X X X X X

Resting EKG X X X X XSerum Triglycerides X X X X X X X X X XSerum Total Cholesterol, HDL, Calculated LDL X X X X X X X X X X

PSYCHOLOGICALNeurobehavioral Assessment

Full X X X X XPsychological Symptoms (SCK-90-R) X X X X X X X X X XQuality of Life Questionnaire X X X X X X X X X X

COMPLIANCE/ADHERENCEAssessment of Adherence (Baseline, quarterly, annually) X X X X X X X X X XDiet History X X X X

*Stereo fluorescein angiography will be performed only in those patients in the primary prevention trial.Note Bene: Assessment of blood glucose control is performed quarterly. Stereo fundus photography is performed at baseline, six months post-randomization, and every sixmonths thereafter. Assessment of blood pressure, pulse and adherence are performed quarterly.

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receive standard therapy, these studies suggest that 50% of subjects will develop retinopathy (atleast 1 microaneurysm) after an additional 3.5 years of followup in the trial. Under an exponential

model, this corresponds to a constant annual hazard rate of about = 0.20 per year of followup.In the secondary intervention trial of subjects with one to 15 years duration of IDDM and minimalretinopathy on entry, the prospective study of Klein, et al (1984) suggests that about 20% ofsubjects who receive standard therapy will progress (three steps on the DCCT retinopathy scale)

after two additional years of followup, and 65% after six years. This also corresponds to aconstant annual hazard rate of about = 0.20 per year of followup.

Thus, for both the primary prevention and secondary intervention trials, it is estimated thatthe hazard rate for retinopathy would be approximately = 0.20 per year of followup in the DCCTamong subjects treated in the standard therapy group. In both the primary prevention andsecondary intervention trials, a hazard rate of = 0.20 implies that about 45% of these subjectswill show progression of retinopathy after three additional years of followup in the DCCT, 63% afterfive years, and 75% after seven years.

3.3 Study Duration and Sample Size

Based on the assumption of = 0.20 for both the primary prevention and secondaryintervention trials, it was then possible to consider the period of recruitment, total study durationand total sample size. This is a recursive process, however, because the power of study dependsupon the total number of events to be observed which is influenced by all three of the abovefactors. After considering various combinations, it was decided that a study of 1400 patients total,700 in each of the primary prevention and secondary intervention trials, the remainder recruitedover a three year period, and with followup for an additional five years, would provide excellentpower to detect clinically meaningful differences between the treatment groups.

In order to provide an accurate description of the cumulative incidence of the onset of

retinopathy within the primary prevention trial and of the progression of retinopathy in thesecondary intervention trial, it was decided that the minimum period of followup for all subjectswould be five years. In addition, it was decided that a three year period of recruitment would beprovided for the 21 Phase II clinics and that it would be expected that these clinics would recruit atotal of 1156 subjects, including those already recruited during Phase II.

In addition, new clinics will be added to the study group which will be expected to recruit244 additional subjects over a two year period. The last subjects to be recruited will enter the trialin September 1988, and since all subjects will be followed for at least five years, this means thatthese last subjects will complete followup in September 1993.

Thus the total sample size objective for the DCCT is 1400 subjects, 700 in each of theprimary prevention and secondary intervention trials, with a minimum duration of followup for allsubjects of five years. However, since some subjects were recruited into Phase II in August 1983,followup of all subjects until September 1993 entails that some subjects will be followed for up toten years. Therefore, the length of followup for each subject will range from five to ten years,depending on when the subject entered the trial. The average duration of followup will be sevenyears.

The study will actually comprise three cohorts of subjects: the Phase II subjects recruitedwithin the original 21 clinics, the Phase III subjects recruited in the original 21 clinics, and the

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Phase III recruited among the new clinics. For each cohort, the following presents the timeintervals of recruitment, the length of the recruitment period, the total duration of study for eachcohort, and the expected sample sizes to be recruited.

Cohort

Recruitment

Interval

RecruitmentPeriod

(years)

StudyPeriod

(years)

Sample Size

Primary Secondary

1) Phase II, 8/83 3/84 0.5 10.0 110 16821 clinics

2) Phase III, 3/85 3/88 3.0 8.5 468 41021 clinics

9/86 9/88 2.0 7.0 122 122TOTAL 700 700

Thus the first few subjects recruited into Phase II in August 1983 will have been followed for tenyears; the first subjects recruited by the original 21 clinics into Phase III will be followed for 8.5

years; and the first subjects recruited by the new clinics will be followed for seven years. The lastsubject recruited by the new clinics will be followed for 5 years. For all subjects combined, thefollowing presents the numbers of subjects expected to be followed for varying durations:

> 5 years: all 1400 subjects> 6 years: 1172 of the 1400 subjects> 7 years: 798 of the 1400 subjects> 8 years: 426 of the 1400 subjects> 9 years: 278 of the 1400 subjects

Since the majority of the subjects will be followed for at least seven years, this will allowaccurate description of the cumulative incidence curves within the standard treatment group over

the first seven years of followup, by which time the cumulative incidence for the onset orprogression of retinopathy is expected to reach 75% based on a hazard rate of = 0.20 per yearof followup.

3.4 Power

In the final analysis of the DCCT data, the cumulative incidence curves will be estimated bythe life-table method for the standard and experimental groups and the curves compared using thelinear rank test. Lachin and Foulkes (1986) describe the evaluation of the power of the linear ranktest using the exponential model for the detection of differences between the cumulative incidencecurves for two groups, where the subjects are recruited in two or more cohorts, with allowancesboth for losses to followup and for non-compliance. In this context, losses to followup are subjects

for whom endpoint evaluations (fundus photographs) are no longer available, whereas non-compliance refers to subjects who did not fully comply with the assigned regimen but who continuefollowup in the trial.

The principal determinant of the power of the linear rank test is the minimal differencebetween the hazard rates for the two groups which it is desired to detect. It must be emphasizedthat it is of interest to the trial to detect either a significant increase or decrease in the incidence ofonset or of progression of retinopathy. Thus, a two-sided test of significance is to be employed.

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However, for purposes of examining a difference in hazard rates, it is more conservative toconsider a reduction in the hazard rate for the experimental group rather than an increase in thehazard rate.

As described above, it is estimated that the hazard rate for the standard treatment group ineither the primary prevention or the secondary intervention trial is expected to be = 0.20 per

year of followup. The trial was then designed to provide a high degree of power to detect areduction in the hazard rate of onset or progression of retinopathy in the experimental treatmentgroup from = 0.20 to the range 0.135 > > 0.125 per year of followup, i.e., a 32.5% to 37.5%reduction in the annual hazard rate. The cumulative incidence as a function of years of followup foreach of these hazard rates is as follows:

Standard Experimentalt __________

yearsfollowup = 0.20 = 0.135 = 0.125

1 0.18 0.13 0.12

2 0.33 0.24 0.22

3 0.45 0.33 0.31

4 0.55 0.33 0.31

5 0.63 0.51 0.46

6 0.70 0.56 0.53

7 0.75 0.61 0.58

Since all 1400 subjects will be exposed for five years of followup, 1172 for six years, 798for seven years, etc., it is possible to estimate the overall simple proportions of subjects in whomthe onset or progression of retinopathy will be observed in each group. The following are the

simple proportions expected to be observed in the standard group ( = 0.20) and in theexperimental group (0.135 > > 0.125), assuming 0% and 10% losses to followup, and assuming0% and 20% non-compliance:

Expected Simple Proportions% losses / % non-compliance Standard Experimental

= 0.20 = 0.135 = 0.125

0% / 0% 0.77 0.63 0.61

10%/ 0% 0.72 0.58 0.56

10%/20% 0.72 0.61 0.58

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Note that 10% losses to followup results in a constant reduction in the expected proportions foreach group, whereas 20% non-compliance results in a narrowing of the difference between theexpected proportions for the standard and experimental groups.

Table 3.1 presents the power of the primary prevention and secondary intervention trials todetect the above minimal differences in hazard rates with the above corresponding reductions in

the cumulative incidence, or simple proportions, of onset and of progression of retinopathy. Poweris presented both assuming a two-sided test at the 0.05 significance level and also at the 0.01significance level. The first column presents the power of the study if it is assumed that there areno subjects who are lost to followup and all subjects are fully compliant. In this case, the study isalmost certain to detect differences at these levels in the cumulative incidence curves for the twotreatment groups. It is unrealistic to expect, however, that all subjects will continue followup andthat all subjects will comply. The next column presents the power of the study assuming that 10%of subjects are lost to followup, but that all subjects who continue treatment fully comply with theassigned regimen. In this case, the power is slightly reduced due to the loss of 10% of subjectsover the period of study, but the study would still have excellent power to detect these differences.The final column, however, presents a more realistic assessment of power which includes anallowance for 10% of subjects being lost to followup and 20% of subjects failing to comply with the

assigned regimen. In this case, both the primary prevention and secondary intervention trialswould provide excellent power (>0.90) for the detection of a 37.5% reduction in the hazard ratefrom 0.20 to 0.125 using either the 0.05 or the 0.01 significance level. If a 0.05 significance level isemployed, the study also provides excellent power (0.91) to detect a 32.5% reduction in thehazard rate from 0.20 to 0.135. However, using the 0.01 significance level, the power of the studywill be good, but not excellent, (0.77) to detect this smaller reduction in the hazard rate.

3.5 Interim Assessments

The plan described above indicates that the study will have excellent power to detectmeaningful differences between the treatment group .us provided that the stated assumptions

apply. These assumptions are that the hazard rate for the onset of retinopathy in the primaryprevention trial is 0.20 per year, the hazard rate for the progression of retinopathy in the secondaryintervention trial is also 0.20 per year, all additional patients are recruited during the allocatedintervals, no more than 10% of patients are lost to followup, and no more than 20% of patients arenon-compliant. Each of the above parameters will be monitored by the Study Group as the studyprogresses. If it is determined that one or more of these assumptions are not accurate, thenadjustments will be implemented to insure that the excellent power of the study will be maintained.Such adjustments may entail a change in the target sample size for either the primary preventionor secondary intervention trials, or a change in the duration of followup. For example, morepatients and/or a longer study duration may be required if the observed hazard rate in either theprimary prevention or secondary intervention trial is substantially less than 0.20 per year.Conversely, fewer patients and/or a shorter duration of followup may be required if the hazard rate

is substantially greater than 0.20 per year.

3.6 Summary

The target sample size for the DCCT is 700 subjects for each of the primary prevention andsecondary intervention trials. The principal outcome is the rate of onset of retinopathy in theprimary prevention trial, and the rate of progression of retinopathy in the secondary intervention

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trial. The cumulative incidence of these events will be described by life-table analyses. Suchanalyses can be summarized by the hazard rate which is the probability of new events per year offollowup. The hazard rate is expected to be 0.20 per year for the standard group in both theprimary prevention and secondary intervention trials. The DCCT has been designed to detect a32.5%-37.5% change in the hazard rate in the experimental group. Allowing for 10% of subjectsbeing lost to followup and 20% of subjects not complying with therapy, the study provides power

>0.91 to detect these changes with a test at the 0.05 significance level (two-tailed) in both theprimary prevention and secondary intervention trials. For a test at the 0.01 level (two-tailed), thestudy provides power = 0.77 to detect the smaller 32.5% change in the hazard rate, and power =0.91 to detect the larger 37.5% change in the hazard rate. The assumptions on which thesecalculations of power are based (hazard rate of 0.20 per year, full recruitment in three years, nomore than 10% lost to followup, and no more than 20% non-compliance) will be monitored duringthe trial, and the target sample size or study duration may be modified if actual experience in theDCCT differs from these estimates.

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REFERENCES

1. Diabetic Retinopathy Research Group: Report 7. A modification of the Airlie Houseclassification of diabetic retinopathy. Invest Ophthalmol Vis Sci 21/2:244-51, 1981.

2. Frank RN, Hoffman WH, Podgor MJ, et al. Retinopathy in juvenile-onset diabetes of shortduration. Ophthal 87:1-9, 1980.

3. Palmberg P, Smith M, Waltman S, et al. The natural history of retinopathy in insulin-dependentjuvenile-onset diabetes. Ophthal 88:613-8, 1981.

4. Klein R, personal communication based on the study described in: Klein R, Klein BE, Moss SE,et al. Prevalence of diabetes mellitus in southern Wisconsin. Am J Epidemiol 119:54-61, 1984.

5. Lachin J. Introduction to sample size determination and power analysis for clinical trials.Controlled Clinical Trials 2:93-113, 1981.

6. Lachin J and Foulkes M. Evaluation of sample size and power for analyses of survival withallowances for non-uniform subject entry, losses to followup, non-compliance and stratification.Biometrics, 42:507-519,1986.

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4. SUBJECT SELECTION AND RECRUITMENT

4.1 Introduction

Investigators at each participating clinical center will determine by a series of screeninginterviews and examinations whether a potential study participant is eligible for inclusion in theDCCT. Each clinical center will recruit individuals for the primary prevention and the secondaryintervention trials.

4.2 Eligibility Criteria

The following conditions must be satisfied for a volunteer to be considered eligible for thePhase III study.

4.2.1 Eligibility Criteria Applicable to All Subjects

1. Age greater than or equal to 13 years and less than 40 years at time of randomization.Adolescents must be at or beyond the Tanner Stage II level of pubertal development.

2. An HbA1c value greater than three standard deviations above the mean of a sample ofnon-diabetic persons (6.55). This criterion is based on the first measurement obtainedduring the pre-randomization evaluation process and exclusion on its basis isapplicable for a period of six months. If, in the opinion of the investigator the value isclearly inconsistent with self blood glucose measurements or local HbA1c values, asecond measurement can be obtained within two weeks of notification of the first value.

3. Informed consent from participants 18 years or older. Informed consent fromparticipants aged less than 18 years and, additionally, informed consent from theparent or guardian.

4. Serum creatinine less than or equal to 1.2 mg/dl, or, at investigators discretion,creatinine clearance greater than or equal to 100 ml/min/1.73m2.

4.2.2 For Subjects Without Retinopathy

1. Duration of IDDM for at least one year but less than or equal to five years.

2. Absence of diabetic retinopathy or other ocular lesions which would confound theassessment of retinopathy or other aspects of ocular status based on central grading ofstereo fundus photographs.

3. Visual acuity of 50 letters (20/25 Snellen equivalent) or better in both eyes (bestcorrected) using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuitycharts and protocol.

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4. Less than 40 mg. albumin/24 hour on a four-hour standardized urine collection.

4.2.3 For Subjects With Minimal Background Retinopathy

1. Duration of IDDM for at least one year but less than or equal to 15 years.

2. Presence of at least one microaneurysm in either eye with or without other diabetesrelated lesions, but less retinopathy than would characterize either eye as P24 or worsebased on central grading of stereo fundus photographs.

3. Visual acuity of 45 letters (20/32 Snellen equivalent) or better in both eyes (bestcorrected) using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuitycharts and protocol.

4. Less than or equal to 200 mg. albumin/24 hour on a four-hour standardized urinecollection.

4.3 Exclusion Criteria

In order to be eligible for this study, the subject must be free of the excluding diseases andconditions itemized below. For some of these diseases, the diagnosis can be made on objectivegrounds. In other cases, it will not be possible to follow rigid criteria, and the diagnosis must restupon the considered judgment of the examining physician. Hospital records will be used asextensively as possible to document the historical material reported by the subject. Some of theseconditions will exclude the subject permanently from the study. Other conditions may onlytemporarily exclude, and the subject may be reconsidered for eligibility for the study at some laterdate.

4.3.1 Exclusion Criteria Applicable to All Subjects

1. Clinical characteristics of IDDM but subjects with more than five years duration of IDDMare excluded if their centrally measured basal or stimulated C-peptide is greater than .2pmol/ml. Subjects with five years or less duration of IDDM are excluded if theircentrally measured stimulated C-peptide is greater than .5 pmol/ml or basal C-peptideis greater than .2 pmol/ml. The basal specimens are considered stimulated if thecentrally measured basal blood glucose is greater than 150 mg/dl.

2. Previous treatment for IDDM with either three or more daily injections of insulin or withan insulin infusion pump except for periods of less than four weeks to manage anintercurrent illness or to determine optimal blood glucose control. An exception will bemade for women who used intensive therapy only during a pregnancy and/or planning

4Classification of eyes is based on Diabetic Retinopathy Study (DRS) criteria. Eyes with newvessels are worse than P2. Eyes without new vessels which meet specified criteria areclassified as P2. Standard photos are those of the Modified Airlie House Classification.

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for the pregnancy and who will have been on one or two injections of insulin for at leastthe year prior to randomization.

3. Insulin Resistance: Requirement of a total of more than two units per kilogram of bodyweight except during intercurrent illnesses lasting less than one month.

4. Three or more documented episodes of diabetic ketoacidosis requiring hospitalizationduring the 12 months prior to the time of randomization.

5. Women who are pregnant or who plan or desire a pregnancy within two years of thetime of randomization.

6. Hypertension

a) Subjects who required treatment of hypertension during the two years prior to thetime of randomization are ineligible for the trial.

b) In adults, sitting blood pressure greater than 140 systolic or 90 diastolic without

treatment at the time of the eligibility history and physical examination.

c) In adolescents, sitting blood pressure greater than the 95th percentile above themean for proper category of age and sex as defined in the Report of the Task Forceon Blood Pressure in Children5.

7. Lipids

a) 2 History of treatment for hyperlipidemia not secondary to diabetes.

b) Serum cholesterol greater than three standard deviations above the mean for sexand age as defined in the Lipid Research Clinic Population Studies Data Book

Volume I of the Prevalence Study.

c) Calculated LDL-cholesterol greater than 190 mg/dl when total serum cholesterol isbelow the mean plus three standard deviations but greater than 265 mg/dl.

8. Active urinary tract infection as indicated by urine abnormalities specified in the Manualof Operations.

9. History of alcoholism or drug abuse during the five years prior to randomization asdefined by the DSM III classification for substance abuse as defined in the Manual ofOperations.

10. Any non-diabetic condition that potentially limits life expectancy or that will interfere withparticipation in the study.

11. Residence at a distance from the clinic that presents a likely impediment to completefollowup or a planned permanent move outside of North America.

5Pediatrics, Vol. 59, Supplement 1, 1977.

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12. Any form of hemoglobinopathy or hemolytic process which interferes with reliableassessment of diabetic control with conventional assays for glycosylated hemoglobin(e.g., sickle trait).

13. Diabetic Neuropathy - Subjects requiring or requesting treatment for diabeticneuropathy at the time of entry into the trial.

14. Previous or current endocrine disorder other than diabetes, corrected primaryhypothyroidism, or functional menstrual disorders. Persons with correctedhyperthyroidism with greater than two years of an euthyroid state at the time ofrandomization and no past or present ophthalmopathy are eligible to be in the DCCT.

15. Obesity defined as a body weight greater than 130% of the ideal body weight asdefined by the 1983 Metropolitan Height and Weight Tables for Men and Women andadjusted for frame size as defined in the DCCT Manual of Operations. Tables aretaken from the data of the 1979 Build Study, Society of Actuaries and Association ofLife Insurance Medical Directors of America, 1980 (see the Manual of Operations).

16. Chronic disease requiring prescription medication for more than a total of four monthsduring the twelve months prior to randomization. (See the Manual of Operations for adetailed list of excluding medications and disqualifying diseases.)

17. Major electrocardiographic abnormalities or clinical history of ischemic (coronary) heartdisease or subjects with symptomatic peripheral vascular disease.

18. History of epilepsy or seizures (not caused by hypoglycemia) requiring medicationduring the five years prior to randomization.

19. Psychological and Behavioral Criteria

a) Psychological problems such as psychotic, neurotic or personality disorders andconditions that will interfere with the ability to maintain complete followup andadhere to the Protocol, or

b) A recent pattern of behavior that, in the opinion of the Principal Investigator,indicates a high likelihood of non-compliance, e.g., missed appointments during thepre-randomization phase or inability to follow other instructions such as thosedetailed in the Manual of Operations.

20. Siblings, parents, children, spouses, or other household members (a) of subjects whohave been randomized into Phase II or III, or (b) of clinic staff members. Clinical centerstaff members are also excluded.

21. Participation in another clinical trial or any study which may interfere with participationin this trial.

22. Any condition or use of any medication which will interfere with the application oftreatment as outlined in the Protocol.

23. For adolescents, history of or demonstrated failure to maintain normal growth anddevelopment two years prior to randomization for any reason, i.e., growth velocity less

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than the third percentile of normal for age, sex and pubertal stage according to theNational Center for Health Statistics Growth Curves for Children, Birth - 18 years,United States, Vital and Health Statistics, DHEW Publication, No. 78-1650, November1977 (see the Manual of Operations). If previous reliable growth records are notavailable, failure to maintain growth at a rate of at least 4 cm. or 1.60 inches per yearduring the previous six months unless pubertal stage (i.e., menarche in females and

Tanner IV in males) indicates that growth is complete.

24. Hypoglycemia

a) 2 More than two hypoglycemic seizures and/or comas during the previous twoyears.

b) More than one hypoglycemic episode in the past two years resulting in cerebralimpairment (e.g., coma, severe confusion, seizure) before the development ofwarning symptoms of hypoglycemia while awake (e.g., excessive sweating,tremors, etc.).

25. The presence of significant chorioretinal scars, optic atrophy, retinal degeneration, orother conditions which might confound the assessment of ocular status.

26. Aphakia in one or both eyes or prior ocular surgery other than strabismus or lid surgery.

27. Intraocular pressure greater than or equal to 23 mm of mercury in one or both eyes, orglaucoma requiring medication.

28. Rubeosis iridis in one or both eyes.

29. Myopia of greater than 7 diopters in one or both eyes.

30. Chronic requirement for any ocular medication.

31. The inability to obtain adequate quality stereo fundus photographs.

32. Prior photocoagulation.

4.3.2 Exclusion Criteria for Subjects Without Retinopathy

The presence of diabetic retinopathy manifested by any one of the following lesions oncentral grading of stereo fundus photographs or clinical exam.

1. Microaneurysms

2. Hemorrhages

3. Hard exudate

4. Soft exudate

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5. Intraretinal microvascular abnormalities (IRMA)

6. Venous caliber abnormalities

7. Arteriolar abnormalities

8. New blood vessels or fibrous proliferation

9. Vitreous or pre-retinal hemorrhage

10. Retinal edema

4.3.3 Additional Exclusion Criteria for Subjects With Minimal Background Retinopathy

The presence of diabetic retinopathy sufficient to categorize either eye as P2 or worsebased on central grading of stereo fundus photographs.

Macular edema defined as definite thickening of the retina within one disc diameter of thecenter of the macula (even if the visual acuity is not yet reduced), as assessed by stereo fundusphotography.

4.4 Recruitment

It is not necessary that individuals be referred to the study by a physician; subjects mayrefer themselves. Each subject must agree, however, that all diabetes care will be provided by theDCCT clinical center health care team.

A recruitment program will be initiated by the DCCT whereby each clinical center willemploy recruitment strategies selected among various options best suited to that clinic. Thesestrategies may include advertisement in the mass media of the trials need for volunteers.

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5. INFORMED CONSENT

5.1 General Principles

In order to be eligible for the trial, each participant must be willing to sign a statement ofinformed consent prior to randomization. This will document the agreement of the subject toparticipate in the study activities. For subjects less than 18 years old, a parent or guardian mustalso sign the informed consent statement.

The basic elements of the informed consent are:

1. A straightforward statement that the study involves research and a clear explanationof the purpose of the trial, including a description of the procedures to be followed inthe screening, eligibility determination, baseline and follow-up examinations as well

as those procedures to be followed in the two treatment regimens, and theidentification of experimental procedures, the method of treatment assignment, andthe expected duration of the subjects participation.

2. A description of the outcome(s) of primary interest, the length and schedules oftreatment and followup, and methods of locating and following up subject participantswho transfer to inactive status.

3. A description of the attendant and reasonably foreseeable discomforts and risks, aswell as a description of any reasonably expected benefits.

4. A disclosure of alternative procedures that might be advantageous for the subject.

5. A statement that participation is voluntary and the subject is free to refuse toparticipate or withdraw consent and to discontinue participation in the project oractivity at any time without jeopardizing his/her medical care.

6. No exculpatory language through which the subject is made to waive, or appear towaive, any of his legal rights, or to release the institution or its agents from liability fornegligence.

7. A description of the measures taken to ensure confidentiality of subject information.

8. A description of the measures taken to ensure subject safety.

9. An explanation of a subjects rights to compensation for research-related injuries andidentification of specific individuals to contact regarding injury and/or questionsrelated to rights as a research subject.

10. A description of subject responsibilities, including an explanation of the informationthat will be available during and at the conclusion of the trial.

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11. An offer to answer all inquiries concerning participation in the research includingidentification of specific individuals to contact for answers to pertinent questionsabout the research.

12. A statement that participation in the study may involve risks which are currentlyunforeseeable.

13. An explanation of circumstances under which the subjects participation may beterminated by the investigator without regard to the subjects consent.

14. An explanation of the health consequences of a subjects decision to withdraw fromthe research and the need for orderly termination of participation.

15. A statement that significant new findings developed during the course of the studywhich may influence the subjects willingness to continue participation will beprovided to the subject.

In accordance with DHHS policy on informed consent, it is necessary "to recognize that

each subjects mental and emotional condition is important .... and that in discussing the elementof risk a certain amount of discretion must be employed consistent with full disclosure of factsnecessary to any informed .footnote consent.6"

The Steering Committee recognizes that individual collaborating clinical centers mayrequire that the recommended Informed Consent Form be amended to include additionalstatements or be reworded to clarify existing statements. All such modifications to the InformedConsent Form will be reviewed, and those which retain and do not detract from the content ofthe suggested DCCT Informed Consent Form will be approved. In addition, copies of signedInformed Consent Forms will be kept in a locked fire-proof safe in the Coordinating Center.

5.2 Sequence of Procedures

A two-stage informed consent procedure is part of a multi-level screening process. It isdesirable that the Principal Investigator or the DCCT physician who will care for the subject beinvolved in the early stages of the sequence. The first Informed Consent Form obtains thesubjects permission, and in the case of adolescents, the parents permission, for the eligibilitytests to be performed.

The second Informed Consent Form obtains the subjects permission, and in the case ofadolescents, the parents permission, to participate in the clinical trial.

The tools utilized for securing informed consent are the DCCT Recruitment Flyer,

Volunteer Information Handbook, Manual of Diabetes Tests, Terms and Special Procedures,DCCT Slide Presentation, Volunteer Understanding Questionnaire, and Informed ConsentForms Numbers 1 and 2. Appendices A and B contain the Informed Consent Forms Numbers 1and 2.

6Salgo vs. Leland Stanford Jr. University Board of Trustees (154 C.A. 2nd 560; 317 p. 2-1701).

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6. PRE-RANDOMIZATION EVALUATION

6.1 General Principles

After preliminary screening, at the time of the pre-randomization examinations, theprospective participant will be asked for written consent for the standardized history and physicalexamination and other eligibility evaluations. All examinations will be scheduled to coordinate withother pre-randomization requirements to optimize convenience for prospective study participantsand to minimize cost by performing the least expensive tests, and those most likely to yieldabnormal results, first (e.g., dipstick screen for urinary protein before microalbuminuria byradioimmunoassay). Table 6.1 illustrates a way of organizing the pre-randomization evaluations.

Although investigators have the flexibility to arrange the examinations in any order, strictrules (see the Manual of Operations) will be enforced regarding the repeated testing of ineligiblesubjects to prove them eligible.

6.2 Laboratory

The pre-randomization examinations include local clinical laboratory procedures which aregiven in Table 6.1. In addition, some specimens will be sent to the Central BiochemistryLaboratory for determination of eligibility criteria as well as to serve as baseline data.

6.3 Ophthalmologic

1. The pre-randomization ophthalmologic examination consists of the following standardizedprocedures:

2. Visual acuity

3. Intraocular pressure measurement

4. Slit-lamp and ophthalmoscopic examinations

4. Stereo fundus photography consisting of seven standard fields

5. Stereo fluorescein angiography in consenting subjects eligible for the primary preventiontrial.

Original fundus photographs and angiograms will be sent to the Central OphthalmologicReading Unit for determination of photographic quality, subject eligibility, and baseline status.

6.4 Renal

The pre-randomization renal examination consists of the following standardizedprocedures:

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1. Preliminary urine dipstick screen, urinalysis (UA) and urine culture (UC). If UC reveals105 colonies per ml, a repeat culture is obtained. UC is mandatory in females and willbe done for males when indicated by UA (2-4 WBC/hpf);

2. Microalbuminuria (four-hour timed collection)

3. Serum creatinine, albumin

4. Urine creatinine, albumin

5. Creatinine clearance

6. I-125 iothalamate clearance

7. Urine creatinine, sodium and urea nitrogen (24-hour urine collection)

Specimens will be sent to the Central Biochemistry Laboratory for determination ofmicroalbuminuria, creatinine clearance, I-125 clearance, urine creatinine, sodium and urea

nitrogen.

6.5 Neurologic

The pre-randomization neurologic examination consists of the following standardized procedures:

1. Neurological history and physical examination

2. Standing and supine blood pressures and pulse

3. Autonomic nervous system function tests

4. Nerve conduction studies

Autonomic Nervous System Function Tests will be centrally read at the Central AutonomicCoding Unit.

6.6 Cardiovascular

The pre-randomization cardiovascular examination consists of the following standardizedprocedures:

1. History and physical examination

2. Peripheral vascular history and physical examination (performed as part of the medicalhistory and physical examination)

3. Resting EKG

EKGs will be interpreted locally for determination of subject eligibility and the results will bemailed to the Coordinating Center on standardized forms. EKGs determined to be abnormal on thebasis of local reading may be sent to the Central EKG Reading Unit for confirmation. All EKGs on

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eligible subjects will be mailed to the Central EKG Reading Unit for coding. These data